Pain control is of prime importance to anyone treating many different diseases and medical conditions. Proper pain relief imparts significant physiological and psychological benefits to the patient. Not only does effective pain relief mean a smoother more pleasant recovery (e.g., mood, sleep, quality of life, etc.) with earlier discharge from medical/surgical/outpatient facilities, but it may also reduce the probability of the acute pain state progressing to a chronic pain syndrome.
Pain serves an important biological function. It signals the presence of damage or disease within the body and is often accompanied by inflammation (redness, swelling, and/or burning). There are two types of pain based on temporal classification: acute pain and chronic pain. Acute pain refers to pain experienced when tissue is being damaged or is damaged. Acute pain serves at least two physiologically advantageous purposes. First, it warns of dangerous environmental stimuli (such as hot or sharp objects) by triggering reflexive responses that end contact with the dangerous stimuli. Second, if reflexive responses do not avoid dangerous environmental stimuli effectively, or tissue injury or infection otherwise results, acute pain facilitates recuperative behaviors. For example, acute pain associated with an injury or infection encourages an organism to protect the compromised area from further insult or use while the injury or infection heals. Once the dangerous environmental stimulus is removed, or the injury or infection has resolved, acute pain, having served its physiological purpose, ends. As contrasted to acute pain, in general, chronic pain serves no beneficial purpose. Chronic pain results when pain associated with an injury or infection continues in an area once the injury or infection has resolved. Chronic pain may involve injury and changes to the nervous system which is referred to as neuropathic pain. Chronic pain may also involve persistent activation of physiological or nociceptive pathways if the insult is prolonged such as pain associated with certain types of cancer.
There are many painful diseases or conditions that require proper pain and/or inflammation control, including but not limited to rheumatoid arthritis, osteoarthritis, spinal disc herniation (i.e., sciatica), carpal/tarsal tunnel syndrome, lower back pain, lower extremity pain, upper extremity pain, cancer, tissue pain and pain associated with injury or repair of cervical, thoracic, and/or lumbar vertebrae or intervertebral discs, rotator cuff, articular joint, TMJ, tendons, ligaments, muscles, spondilothesis, stenosis, discogenic back pain, and joint pain or the like.
One category of chronic pain is chronic pelvic pain syndromes. Chronic pelvic pain may occur in both men and women of all ages and results from a variety of injuries and disorders. It is a common and debilitating problem that can significantly impair the quality of life of the patient suffering from it. Chronic pelvic pain occurs in the pelvic or lower abdominal region and can last for six months or longer.
In men, chronic pelvic pain may result from chronic idiopathic prostatitis (also referred to as nonbacterial prostatitis or chronic pelvic pain syndrome), chronic bacterial prostatitis or interstitial cystitis where the symptoms typically include in addition to pelvic pain, urinary urgency and frequency, sexual dysfunction and in most cases patients have a hypertonic pelvic floor muscles upon physical examination. The most common treatment for these disorders involves pharmacologic treatments typically orally administered such as antibiotics, anti-inflammatory agents, alpha blockers, anti-spasmodics, analgesics, and muscle relaxants. Alpha blockers have successfully treated symptoms of prostatitis in some patients, although the improvements have been modest and adverse event rates have been significant. Oral muscle relaxants may help decrease pelvic floor tone but often associated with dose-limiting side effects which limit their usefulness.
Other types of chronic pelvic pain experienced by men include chronic testicular pain (CTP), post vasectomy pain, genitofemoral neuralgia and other pain originating from the testicles, groin, or abdomen. The incidence of patients with CTP, also referred to as orchialgia, orchidynia, or chronic scrotal pain, is large and may be caused by on-going inflammation of the testicle (orchitis) or epididymis (epdidymitis), trauma, tumors, hernia, torsion (twisting of the testicle), varicocele, hydrocele, spermatocele polyarteritis nodosa, and previous surgical interventions such as vasectomy and hernia surgery.
Typically, testicle removal and spermatic cord denervation procedures are used to treat CTP. In spermatic cord denervation procedures, nerves in or adjacent to the spermatic cord, i.e., the genitofemoral nerve or sympathetic nerves, are severed or permanently removed. Such procedures may result in permanent and substantial pain relief regardless of the origin of pain. However, severing or removing these nerves may result in loss of sensation in the testicle and/or scrotum, loss of the cremasteric reflex which may cause fertility issues, and even loss of blood flow causing the testicle to die. Therapeutic nerve blocks may also be used to treat CTP, but generally only relieve pain temporarily.
Chronic pelvic pain is also a common medical problem affecting women today. Sources of pain may include injury to nerves resulting from surgical procedures, non-surgical conditions, vulvodynia which can be very debilitating but has no obvious source, and interstitial cystitis (painful bladder syndrome). Surgical procedures that may injure nerves in the pelvic region resulting in pelvic pain may include urological operations in the pelvic area, gynecological surgery, and hysterectomy. Non-surgical conditions which cause pain in women include adhesions, endometriosis, and pelvic congestion. Irritable bowel syndrome may also be considered a chronic pelvic pain condition. Surgical procedures aimed at removing the suspected painful bladder have generally been unsuccessful and often result in worsening of the pain state. This result suggests that the chronic pain state has extended beyond the peripheral organ and may involve central sensitization with the spinal cord that receives sensory input from the peripheral organs.
One known class of pharmaceuticals used to treat pain is opioids. This class of compounds is well-recognized as being among the most effective type of drugs for controlling pain, such as post-operative pain. Unfortunately, because opioids are administered systemically, the associated side effects raise significant concerns, including disabling the patient, depressing the respiratory system, constipation, and psychoactive effects such as sedation and euphoria, thereby instituting a hurdle to recovery and regained mobility. Consequently, physicians typically limit the administration of opioids to within the first twenty-four hours post-surgery. Although opioids may be used to manage severe episodes of chronic pelvic pain, chronic opioid use may be associated with the development of tolerance leading to the need for higher doses to produce sustained analgesic effects. They may also be associated with addiction.
One class of pharmaceutical agents are benzodiazepines, which act on the central nervous system to produce various levels of sedative-hypnotic, muscle-relaxant, anxiolytic, and anticonvulsant effects. The members of this class function by interacting with various subunits of the GABAA receptor that regulates the flux of chloride ions across neuronal cell membranes. Benzodiazepines do not directly activate the GABAA receptors but instead modulate the receptor thereby enhancing the effects of the endogenous agonist, gamma-amino-butyric acid (GABA); GABA is the major inhibitory neurotransmitter in the central nervous system. As a class, benzodiazepines are all lipophilic in the nonionized state. Benzodiazepines are often subcategorized by their duration of effect from ultra-short acting to long-acting agents and are available in oral, intramuscular, intravenous, and rectal formulations. Specific drugs that are members of the benzodiazepine class include alprazolam, chlordiazepoxide, clonazeparn, chlorazepate, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, and triazilam.
One specific benzodiazepine that is well known to the medical profession is midazolam, which is widely recognized as an ultra short-acting benzodiazepine derivative. It has potent anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties. In general, midazolam, also referred to as 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (C18H13ClFN3), may be represented by the following chemical structure:

Midazolam has been used historically to produce both local and regional anesthesia. Midazolam acts on the benzodiazepine binding site of GABAA receptors. When bound it enhances the binding of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system. It can be administered intraspinally (epidural or intrathecal) to treat the spinal cord and provide analgesia for pelvic operations, child delivery, and post surgical recovery. Midazolam is only available as injectable formulations.
There is a need to develop effective formulations of this class of compounds for this application that provide sustained release of benzodiazepines, such as midazolam, thereby provided prolonged pain relief.